1. Field of the Invention
The present invention relates the development of potent biomodal antioxidant small molecules capable of beta-amyloid prevention and disaggregation and for targeting metal-based oxidative stress in neurodegenerative disorders.
2. Description of the Prior Art
Alzheimer's disease (AD) is a debilitating disease that affects over 5.4 million people currently, at an annual cost exceeding 180 billion dollars in the U.S. alone. Physiological and molecular features include the deposition of beta-amyloid (Aβ) plaques, elevated levels of transition metals and oxidative stress. The exact mechanism leading to AD is still not-established, although amyloid is a component in many hypotheses proposed to date. Recent attention has implicated metal ions in the cascade leading to the physiological and pathological hallmarks of AD thus forming the “Metal Hypothesis of Alzheimer's Disease”.
Transition metals are trace elements vital for normal biological function because they serve as structural drivers, cofactors or reactive centers in proteins and enzymes. Fenton chemistry is defined by the oxidation of redox active metal ions in their reduced from, such as Fe(II) or Cu(I), with H2O2 to produce radicals that are known to cause DNA oxidation, disruption of mitochondrial membrane potentials, lipid peroxidation. Redox chemistry of these elements is tightly regulated throughout biology via regulatory and chaperone systems, so that protein modification, in conjunction with Fenton chemical reactions, producing cellular oxidative stress will be avoided. Disruptions or alterations in the redox potential of metal-ion regulatory systems have therefore been implicated in a number of disease states to date which include: Huntington's, Alzheimer's, and Parkinson's, Lou Gehrig's disease, as well as macular degeneration and Freidrich's ataxia. For example, a histidine rich binding site has been identified in Aβ1-40 or Aβ1-42. Insoluble beta-amyloid plaques (Aβ) have increased levels of copper, zinc and iron, while intracellular copper stores are deficient in AD patients. Metal ion chelation by amyloid plaques gives rise to concomitant free radical generation, resulting in neuronal death. Furthermore, increased levels of oxidative stress have been, in-part, attributed to alterations in the expression of superoxide dismutase, as well as protein metal-ion chaperones. Modifications in the levels of metal-ion chaperone expression associated with the signal transduction pathway of glutamate receptors, for example, have also been noted with concomitantly higher levels of cleaved amyloid precursor protein to produce Aβ1-40 or Aβ1-42. Finally, aged populations naturally exhibit increased levels of ROS due to decreased levels of antioxidants such as melatonin, resulting in higher levels of oxidative stress. However, AD models suggest more exacerbated levels of ROS, thus resulting in AD progression.
There is no effective or preventative protocol prescribed for AD, nor have proposed therapies found success in symptom alleviation neurodegenerative decline associated with AD. Many hypothetical pathways of AD have been targeted, one taking aim at the metal-based hypothesis proposed by Bush et al. Synthetic targets focused on inhibiting the interactions of Aβ with metal ions, along with atypical metal ion homeostasis are limited by ion specificity, an inability to cross the blood brain barrier (BBB), and/or biological compatibility. A compound finding exception to these roadblocks has been evaluated in Phase II clinical trials. The chelator clioquinol (CQ) provided improved cognition in mouse models, but its widespread use has been terminated by the adverse side effect of subacute myelo-optic neuropathy. The positive effects exhibited by CQ encourage synthetic chemists to pursue the chelator strategy as a route to potentiating the cognitive decline associated with metal-ion mis-regulation and plaque deposition. A second generation congener of CQ, PBT2, has been produced and is in Phase II clinical trials. Studies of this compound showed improved cognition in AD transgenic mice, and demonstrated positive effects on the learning and memory in AD patients. In contrast to this agent serving as a chelator as utilized in the sense of typical metal-overload disorders, i.e., removing excess metal, the authors have shown that these compounds can serve as neuromodulators by restoring the metal-ion imbalance for neurochemical communication pathways involved in synaptic activity. When the “lost” metal ions that lead to Aβ deposition are rescued by these synthetic chaperones, their activities in the communication pathways are restored, and Aβ clearance is elevated.
With these results, the present invention has as one object the pursuit of biologically compatible transition metal-ion ligands as therapy for AD and other related neurodegenerative diseases.